Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTBUV19I)

DOT Name Podoplanin (PDPN)
Synonyms Aggrus; Glycoprotein 36; Gp36; PA2.26 antigen; T1-alpha; T1A
Gene Name PDPN
Related Disease
Metastatic malignant neoplasm ( )
Pancreatic cancer ( )
Adenocarcinoma ( )
Adult glioblastoma ( )
Adult respiratory distress syndrome ( )
Advanced cancer ( )
Bacterial pneumonia ( )
Bone osteosarcoma ( )
Brain neoplasm ( )
Breast cancer ( )
Breast carcinoma ( )
Breast neoplasm ( )
Cervical cancer ( )
Cervical carcinoma ( )
Colorectal carcinoma ( )
Esophageal squamous cell carcinoma ( )
Gastric cancer ( )
Glioma ( )
Head-neck squamous cell carcinoma ( )
Hepatocellular carcinoma ( )
Invasive ductal breast carcinoma ( )
Lung cancer ( )
Lung carcinoma ( )
Lung squamous cell carcinoma ( )
Malignant pleural mesothelioma ( )
Mesothelioma ( )
Non-small-cell lung cancer ( )
Oral cancer ( )
Osteosarcoma ( )
Peritoneal neoplasm ( )
Psoriasis ( )
Rheumatoid arthritis ( )
Squamous cell carcinoma ( )
Stomach cancer ( )
Thyroid gland papillary carcinoma ( )
Thyroid tumor ( )
Venous thromboembolism ( )
Malignant mesothelioma ( )
Lung adenocarcinoma ( )
Melanoma ( )
Nasopharyngeal carcinoma ( )
Oral mucosa leukoplakia ( )
UniProt ID
PDPN_HUMAN
3D Structure
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2D Sequence (FASTA)
Download
3D Structure (PDB)
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PDB ID
3WSR; 4YO0; 5XCV; 7C94; 7CQC; 7CQD
Pfam ID
PF05808
Sequence
MWKVSALLFVLGSASLWVLAEGASTGQPEDDTETTGLEGGVAMPGAEDDVVTPGTSEDRY
KSGLTTLVATSVNSVTGIRIEDLPTSESTVHAQEQSPSATASNVATSHSTEKVDGDTQTT
VEKDGLSTVTLVGIIVGVLLAIGFIGAIIVVVMRKMSGRYSP
Function
Mediates effects on cell migration and adhesion through its different partners. During development plays a role in blood and lymphatic vessels separation by binding CLEC1B, triggering CLEC1B activation in platelets and leading to platelet activation and/or aggregation. Interaction with CD9, on the contrary, attenuates platelet aggregation induced by PDPN. Through MSN or EZR interaction promotes epithelial-mesenchymal transition (EMT) leading to ERZ phosphorylation and triggering RHOA activation leading to cell migration increase and invasiveness. Interaction with CD44 promotes directional cell migration in epithelial and tumor cells. In lymph nodes (LNs), controls fibroblastic reticular cells (FRCs) adhesion to the extracellular matrix (ECM) and contraction of the actomyosin by maintaining ERM proteins (EZR; MSN and RDX) and MYL9 activation through association with unknown transmembrane proteins. Engagement of CLEC1B by PDPN promotes FRCs relaxation by blocking lateral membrane interactions leading to reduction of ERM proteins (EZR; MSN and RDX) and MYL9 activation. Through binding with LGALS8 may participate in connection of the lymphatic endothelium to the surrounding extracellular matrix. In keratinocytes, induces changes in cell morphology showing an elongated shape, numerous membrane protrusions, major reorganization of the actin cytoskeleton, increased motility and decreased cell adhesion. Controls invadopodia stability and maturation leading to efficient degradation of the extracellular matrix (ECM) in tumor cells through modulation of RHOC activity in order to activate ROCK1/ROCK2 and LIMK1/LIMK2 and inactivation of CFL1. Required for normal lung cell proliferation and alveolus formation at birth. Does not function as a water channel or as a regulator of aquaporin-type water channels. Does not have any effect on folic acid or amino acid transport.
Tissue Specificity
Highly expressed in placenta, lung, skeletal muscle and brain. Weakly expressed in brain, kidney and liver. In placenta, expressed on the apical plasma membrane of endothelium. In lung, expressed in alveolar epithelium. Up-regulated in colorectal tumors and expressed in 25% of early oral squamous cell carcinomas.
Reactome Pathway
Specification of primordial germ cells (R-HSA-9827857 )
GPVI-mediated activation cascade (R-HSA-114604 )

Molecular Interaction Atlas (MIA) of This DOT

42 Disease(s) Related to This DOT
Disease Name Disease ID Evidence Level Mode of Inheritance REF
Metastatic malignant neoplasm DIS86UK6 Definitive Altered Expression [1]
Pancreatic cancer DISJC981 Definitive Biomarker [2]
Adenocarcinoma DIS3IHTY Strong Biomarker [3]
Adult glioblastoma DISVP4LU Strong Altered Expression [4]
Adult respiratory distress syndrome DISIJV47 Strong Biomarker [5]
Advanced cancer DISAT1Z9 Strong Biomarker [6]
Bacterial pneumonia DISPW7PH Strong Biomarker [7]
Bone osteosarcoma DIST1004 Strong Altered Expression [8]
Brain neoplasm DISY3EKS Strong Altered Expression [9]
Breast cancer DIS7DPX1 Strong Altered Expression [10]
Breast carcinoma DIS2UE88 Strong Biomarker [11]
Breast neoplasm DISNGJLM Strong Biomarker [12]
Cervical cancer DISFSHPF Strong Altered Expression [13]
Cervical carcinoma DIST4S00 Strong Altered Expression [13]
Colorectal carcinoma DIS5PYL0 Strong Altered Expression [14]
Esophageal squamous cell carcinoma DIS5N2GV Strong Biomarker [15]
Gastric cancer DISXGOUK Strong Altered Expression [16]
Glioma DIS5RPEH Strong Biomarker [17]
Head-neck squamous cell carcinoma DISF7P24 Strong Altered Expression [18]
Hepatocellular carcinoma DIS0J828 Strong Biomarker [19]
Invasive ductal breast carcinoma DIS43J58 Strong Altered Expression [20]
Lung cancer DISCM4YA Strong Altered Expression [21]
Lung carcinoma DISTR26C Strong Altered Expression [21]
Lung squamous cell carcinoma DISXPIBD Strong Altered Expression [21]
Malignant pleural mesothelioma DIST2R60 Strong Altered Expression [22]
Mesothelioma DISKWK9M Strong Altered Expression [23]
Non-small-cell lung cancer DIS5Y6R9 Strong Biomarker [24]
Oral cancer DISLD42D Strong Biomarker [25]
Osteosarcoma DISLQ7E2 Strong Altered Expression [8]
Peritoneal neoplasm DIS2ZMIF Strong Biomarker [26]
Psoriasis DIS59VMN Strong Biomarker [27]
Rheumatoid arthritis DISTSB4J Strong Biomarker [27]
Squamous cell carcinoma DISQVIFL Strong Altered Expression [28]
Stomach cancer DISKIJSX Strong Altered Expression [29]
Thyroid gland papillary carcinoma DIS48YMM Strong Biomarker [30]
Thyroid tumor DISLVKMD Strong Altered Expression [31]
Venous thromboembolism DISUR7CR Strong Biomarker [32]
Malignant mesothelioma DISTHJGH moderate Altered Expression [23]
Lung adenocarcinoma DISD51WR Limited Biomarker [33]
Melanoma DIS1RRCY Limited Biomarker [1]
Nasopharyngeal carcinoma DISAOTQ0 Limited Altered Expression [1]
Oral mucosa leukoplakia DISJTL5X Limited Altered Expression [34]
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⏷ Show the Full List of 42 Disease(s)
Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DOT
14 Drug(s) Affected the Gene/Protein Processing of This DOT
Drug Name Drug ID Highest Status Interaction REF
Valproate DMCFE9I Approved Valproate increases the expression of Podoplanin (PDPN). [35]
Calcitriol DM8ZVJ7 Approved Calcitriol increases the expression of Podoplanin (PDPN). [36]
Triclosan DMZUR4N Approved Triclosan increases the expression of Podoplanin (PDPN). [37]
Menadione DMSJDTY Approved Menadione increases the expression of Podoplanin (PDPN). [38]
Panobinostat DM58WKG Approved Panobinostat increases the expression of Podoplanin (PDPN). [39]
Cytarabine DMZD5QR Approved Cytarabine decreases the expression of Podoplanin (PDPN). [40]
SNDX-275 DMH7W9X Phase 3 SNDX-275 increases the expression of Podoplanin (PDPN). [39]
Belinostat DM6OC53 Phase 2 Belinostat increases the expression of Podoplanin (PDPN). [39]
(+)-JQ1 DM1CZSJ Phase 1 (+)-JQ1 decreases the expression of Podoplanin (PDPN). [42]
PMID28460551-Compound-2 DM4DOUB Patented PMID28460551-Compound-2 decreases the expression of Podoplanin (PDPN). [43]
PMID26394986-Compound-22 DM43Z1G Patented PMID26394986-Compound-22 decreases the expression of Podoplanin (PDPN). [44]
Bisphenol A DM2ZLD7 Investigative Bisphenol A increases the expression of Podoplanin (PDPN). [45]
Trichostatin A DM9C8NX Investigative Trichostatin A increases the expression of Podoplanin (PDPN). [46]
Nitrobenzanthrone DMN6L70 Investigative Nitrobenzanthrone decreases the expression of Podoplanin (PDPN). [47]
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⏷ Show the Full List of 14 Drug(s)
1 Drug(s) Affected the Post-Translational Modifications of This DOT
Drug Name Drug ID Highest Status Interaction REF
Benzo(a)pyrene DMN7J43 Phase 1 Benzo(a)pyrene decreases the methylation of Podoplanin (PDPN). [41]
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References

1 Blocking podoplanin suppresses growth and pulmonary metastasis of human malignant melanoma.BMC Cancer. 2019 Jun 17;19(1):599. doi: 10.1186/s12885-019-5808-9.
2 Impact of Extravasated Platelet Activation and Podoplanin-positive Cancer-associated Fibroblasts in Pancreatic Cancer Stroma.Anticancer Res. 2019 Oct;39(10):5565-5572. doi: 10.21873/anticanres.13750.
3 Organoid culture containing cancer cells and stromal cells reveals that podoplanin-positive cancer-associated fibroblasts enhance proliferation of lung cancer cells.Lung Cancer. 2019 Aug;134:100-107. doi: 10.1016/j.lungcan.2019.04.007. Epub 2019 Apr 8.
4 Podoplanin expression is a prognostic biomarker but may be dispensable for the malignancy of glioblastoma.Neuro Oncol. 2019 Feb 19;21(3):326-336. doi: 10.1093/neuonc/noy184.
5 Platelet CLEC-2 protects against lung injury via effects of its ligand podoplanin on inflammatory alveolar macrophages in the mouse.Am J Physiol Lung Cell Mol Physiol. 2017 Dec 1;313(6):L1016-L1029. doi: 10.1152/ajplung.00023.2017. Epub 2017 Aug 24.
6 Deficiency of the adrenomedullin-RAMP3 system suppresses metastasis through the modification of cancer-associated fibroblasts.Oncogene. 2020 Feb;39(9):1914-1930. doi: 10.1038/s41388-019-1112-z. Epub 2019 Nov 21.
7 A type I cell-specific protein is a biochemical marker of epithelial injury in a rat model of pneumonia.Am J Physiol. 1995 Feb;268(2 Pt 1):L181-6. doi: 10.1152/ajplung.1995.268.2.L181.
8 Platelets and cancer-associated thrombosis: focusing on the platelet activation receptor CLEC-2 and podoplanin.Blood. 2019 Nov 28;134(22):1912-1918. doi: 10.1182/blood.2019001388.
9 Venous Thromboembolism in Brain Tumors: Risk Factors, Molecular Mechanisms, and Clinical Challenges.Semin Thromb Hemost. 2019 Jun;45(4):334-341. doi: 10.1055/s-0039-1688493. Epub 2019 Apr 30.
10 Intensity and Pattern of Enhancement on CESM: Prognostic Significance and its Relation to Expression of Podoplanin in Tumor Stroma - A Preliminary Report.Anticancer Res. 2018 Feb;38(2):1085-1095. doi: 10.21873/anticanres.12327.
11 Podoplanin-positive Cancer-associated Stromal Fibroblasts in Primary Tumor and Synchronous Lymph Node Metastases of HER2-overexpressing Breast Carcinomas.Anticancer Res. 2018 Apr;38(4):1957-1965. doi: 10.21873/anticanres.12433.
12 Detection of lymphovascular invasion in early breast cancer by D2-40 (podoplanin): a clinically useful predictor for axillary lymph node metastases.Breast Cancer Res Treat. 2008 Dec;112(3):503-11. doi: 10.1007/s10549-007-9875-2. Epub 2007 Dec 29.
13 Inflammatory Cytokines Induce Podoplanin Expression at the Tumor Invasive Front.Am J Pathol. 2018 May;188(5):1276-1288. doi: 10.1016/j.ajpath.2018.01.016. Epub 2018 Feb 17.
14 Podoplanin expression identified in stromal fibroblasts as a favorable prognostic marker in patients with colorectal carcinoma.Oncology. 2009;77(1):53-62. doi: 10.1159/000226112. Epub 2009 Jun 25.
15 The expression of podoplanin protein is a diagnostic marker to distinguish the early infiltration of esophageal squamous cell carcinoma.Oncotarget. 2017 Mar 21;8(12):19013-19020. doi: 10.18632/oncotarget.14596.
16 Podoplanin Expression as a Prognostic Factor in Gastric Cancer.Anticancer Res. 2018 May;38(5):2717-2722. doi: 10.21873/anticanres.12513.
17 Podoplanin Positive Myeloid Cells Promote Glioma Development by Immune Suppression.Front Oncol. 2019 Mar 26;9:187. doi: 10.3389/fonc.2019.00187. eCollection 2019.
18 Correlation between podoplanin expression and extracapsular spread in squamous cell carcinoma of the oral cavity using subjective immunoreactivity scores and semiquantitative image analysis.Head Neck. 2017 Jan;39(1):98-108. doi: 10.1002/hed.24537. Epub 2016 Jul 20.
19 Evaluation of Podoplanin Expression in Hepatocellular Carcinoma Using RNAscope and Immunohistochemistry - A Preliminary Report.Cancer Genomics Proteomics. 2017 Sep-Oct;14(5):383-387. doi: 10.21873/cgp.20048.
20 Expression of podoplanin in stromal fibroblasts plays a pivotal role in the prognosis of patients with pancreatic cancer.Surg Today. 2018 Jan;48(1):110-118. doi: 10.1007/s00595-017-1559-x. Epub 2017 Jul 12.
21 Podoplanin expression in cancer-associated fibroblasts predicts unfavourable prognosis in patients with pathological stage IA lung adenocarcinoma.Histopathology. 2018 Feb;72(3):490-499. doi: 10.1111/his.13390. Epub 2017 Nov 27.
22 Detection of circulating tumor cells with a novel microfluidic system in malignant pleural mesothelioma.Cancer Sci. 2019 Feb;110(2):726-733. doi: 10.1111/cas.13895. Epub 2019 Jan 8.
23 Therapeutic efficacy evaluation of radioimmunotherapy with (90) Y-labeled anti-podoplanin antibody NZ-12 for mesothelioma.Cancer Sci. 2019 May;110(5):1653-1664. doi: 10.1111/cas.13979. Epub 2019 Mar 12.
24 Link between tumor-promoting fibrous microenvironment and an immunosuppressive microenvironment in stage I lung adenocarcinoma.Lung Cancer. 2018 Dec;126:64-71. doi: 10.1016/j.lungcan.2018.10.021. Epub 2018 Oct 28.
25 Podoplanin emerges as a functionally relevant oral cancer biomarker and therapeutic target.Oral Oncol. 2018 Mar;78:126-136. doi: 10.1016/j.oraloncology.2018.01.011. Epub 2018 Feb 20.
26 Two cases of malignant peritoneal mesothelioma without asbestos exposure: cytologic and immunohistochemical features.Ann Diagn Pathol. 2013 Feb;17(1):99-103. doi: 10.1016/j.anndiagpath.2012.05.007. Epub 2012 Jul 10.
27 Podoplanin in Inflammation and Cancer.Int J Mol Sci. 2019 Feb 6;20(3):707. doi: 10.3390/ijms20030707.
28 Association of the co-expression of SOX2 and Podoplanin in the progression of oral squamous cell carcinomas - an immunohistochemical study.J Appl Oral Sci. 2019 Sep 9;27:e20180348. doi: 10.1590/1678-7757-2018-0348.
29 The clinicopathological significance of Thrombospondin-4 expression in the tumor microenvironment of gastric cancer.PLoS One. 2019 Nov 8;14(11):e0224727. doi: 10.1371/journal.pone.0224727. eCollection 2019.
30 Circulating epithelial cell counts for monitoring the therapeutic outcome of patients with papillary thyroid carcinoma.Oncotarget. 2017 Aug 24;8(44):77453-77464. doi: 10.18632/oncotarget.20512. eCollection 2017 Sep 29.
31 Podoplanin (PDPN) affects the invasiveness of thyroid carcinoma cells by inducing ezrin, radixin and moesin (E/R/M) phosphorylation in association with matrix metalloproteinases.BMC Cancer. 2019 Jan 17;19(1):85. doi: 10.1186/s12885-018-5239-z.
32 Intratumoral platelet aggregate formation in a murine preclinical glioma model depends on podoplanin expression on tumor cells.Blood Adv. 2019 Apr 9;3(7):1092-1102. doi: 10.1182/bloodadvances.2018015966.
33 Prognostic significance of combining immunohistochemical markers for cancer-associated fibroblasts in lung adenocarcinoma tissue.Virchows Arch. 2019 Aug;475(2):181-189. doi: 10.1007/s00428-019-02587-9. Epub 2019 May 27.
34 Podoplanin expression in oral leukoplakiaa prospective study.J Craniomaxillofac Surg. 2019 Mar;47(3):505-509. doi: 10.1016/j.jcms.2018.12.005. Epub 2018 Dec 13.
35 Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
36 Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
37 Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
38 Vitamin K promotes mineralization, osteoblast-to-osteocyte transition, and an anticatabolic phenotype by {gamma}-carboxylation-dependent and -independent mechanisms. Am J Physiol Cell Physiol. 2009 Dec;297(6):C1358-67. doi: 10.1152/ajpcell.00216.2009. Epub 2009 Aug 12.
39 A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
40 Cytosine arabinoside induces ectoderm and inhibits mesoderm expression in human embryonic stem cells during multilineage differentiation. Br J Pharmacol. 2011 Apr;162(8):1743-56.
41 Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
42 Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
43 Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
44 Cyclooxygenase-2 inhibition: effects on tumour growth, cell cycling and lymphangiogenesis in a xenograft model of breast cancer. Br J Cancer. 2007 Feb 26;96(4):575-82. doi: 10.1038/sj.bjc.6603593. Epub 2007 Feb 6.
45 Bisphenol A and bisphenol S induce distinct transcriptional profiles in differentiating human primary preadipocytes. PLoS One. 2016 Sep 29;11(9):e0163318.
46 From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
47 3-Nitrobenzanthrone promotes malignant transformation in human lung epithelial cells through the epiregulin-signaling pathway. Cell Biol Toxicol. 2022 Oct;38(5):865-887. doi: 10.1007/s10565-021-09612-1. Epub 2021 May 25.